Intracellular zinc increase inhibits p53(-/-) pancreatic adenocarcinoma cell growth by ROS/AIF-mediated apoptosis.
We show that treatment with non-toxic doses of zinc in association to the ionophore compound pyrrolidine dithiocarbamate (PDTC) inhibits p53(-/-) pancreatic cancer cell growth much more efficiently than gemcitabine, the gold standard chemotherapeutic agent for pancreatic cancer. Both the metal chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine and the radical scavenger N-acetyl-l-cysteine are able to recover cell growth inhibition by Zn/PDTC, demonstrating that this effect depends on the increased levels of intracellular zinc and of reactive oxygen species (ROS). Zn/PDTC treatment induces a strong apoptotic cell death that is associated to ROS-dependent nuclear translocation of the mitochondrial factor AIF, but not to the regulation of apoptotic genes and caspase activation. Primary fibroblasts are more resistant than pancreatic cancer cells to Zn/PDTC treatment and exhibit a lower basal and Zn/PDTC-induced enhancement of intracellular zinc. We show that Zn/PDTC induces p53 proteasomal degradation and that the proteasome inhibitor MG132 further increases fibroblast growth inhibition by Zn/PDTC, suggesting that p53 degradation plays an important role in fibroblast resistance to Zn/PDTC.
Donadelli
M
M
Department of Morphological and Biomedical Sciences, Section of Biochemistry, University of Verona, Strada Le Grazie, 8, 37134 Verona, Italy.
Dalla Pozza
E
E
Scupoli
M T
MT
Costanzo
C
C
Scarpa
A
A
Palmieri
M
M
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D005029:Ethylenediamines / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D021381:Protein Transport / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013859:Thiocarbamates / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D015032:Zinc / Q000378:metabolism*
D051033:Apoptosis Inducing Factor; D005029:Ethylenediamines; D007976:Leupeptins; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D013859:Thiocarbamates; D016159:Tumor Suppressor Protein p53; C020972:pyrrolidine dithiocarbamic acid; D020169:Caspases; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde